title: AMG 900, pan-Aurora kinase inhibitor, preferentially inhibits the proliferation of breast cancer cell lines with dysfunctional p53.
abstract: Aurora kinases play important roles in cell division and are frequently overexpressed in human cancer. AMG 900 is a novel pan-Aurora kinase inhibitor currently being tested in Phase I clinical trials. We aimed to evaluate the in vitro activity of AMG 900 in a panel of 44 human breast cancer and immortalized cell lines and identify predictors of response. AMG 900 inhibited proliferation at low nanomolar concentrations in all cell lines tested. Response was further classified based on the induction of lethality. 25 cell lines were classified as highly sensitive (lethality at 10 nM of AMG 900 >10 %), 19 cell lines as less sensitive to AMG 900 (lethality at 10 nM of AMG 900 <10 %). Traditional molecular subtypes of breast cancer did not predict for this differential response. There was a weak association between AURKA amplification and response to AMG 900 (response ratio = 2.53, p = 0.09). mRNA expression levels of AURKA, AURKB, and AURKC and baseline protein levels of Aurora kinases A and B did not significantly associate with response. Cell lines with TP53 loss of function mutations (RR = 1.86, p = 0.004) and low baseline p21 protein levels (RR = 2.28, p = 0.0004) were far more likely to be classified as highly sensitive to AMG 900. AMG 900 induced p53 and p21 protein expression in cell lines with wt TP53. AMG 900 caused the accumulation of cells with >4 N DNA content in a majority of cell lines independently of sensitivity and p53 status. AMG 900 induced more pronounced apoptosis in highly sensitive p53-dysfunctional cell lines. We have found that AMG 900 is highly active in breast cancer cell lines and that TP53 loss of function mutations as well as low baseline expression of p21 protein predict strongly for increased sensitivity to this compound in vitro.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Geffen School of Medicine at UCLA, 10833 Le Conte Ave, 11-934 Factor Bldg, Los Angeles, CA, 90095, USA.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Kalous
authors.forename: Dylan
authors.initials: D
authors.lastname: Conklin
authors.forename: Amrita J
authors.initials: AJ
authors.lastname: Desai
authors.forename: Judy
authors.initials: J
authors.lastname: Dering
authors.forename: Jennifer
authors.initials: J
authors.lastname: Goldstein
authors.forename: Charles
authors.initials: C
authors.lastname: Ginther
authors.forename: Lee
authors.initials: L
authors.lastname: Anderson
authors.forename: Ming
authors.initials: M
authors.lastname: Lu
authors.forename: Teodora
authors.initials: T
authors.lastname: Kolarova
authors.forename: Mark A
authors.initials: MA
authors.lastname: Eckardt
authors.forename: Anita
authors.initials: A
authors.lastname: Langerød
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Slamon
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finn
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D064108:Aurora Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015870:Gene Expression; D006801:Humans; D009154:Mutation; D010793:Phthalazines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C555658:N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine; D010793:Phthalazines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C576917:AURKA protein, human; C576921:AURKB protein, human; C576927:AURKC protein, human; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064108:Aurora Kinase C